tbuckley/cabot-search huggingface dataset:
A two-stage genome-wide association study to identify novel genetic loci associated with acute radiotherapy toxicity in nasopharyngeal carcinoma
Authors: Yang Wang, Fan Xiao, Yi Zhao, Chen-Xue Mao, Lu-Lu Yu, Lei-Yun Wang, Qi Xiao, Rong Liu, Xi Li, Howard L. McLeod, Bi-Wen Hu, Yu-Ling Huang, Qiao-Li Lv, Xiao-Xue Xie, Wei-Hua Huang, Wei Zhang, Cheng-Xian Guo, Jin-Gao Li, Ji-Ye Yin
Journal: Molecular Cancer (2022)

Abstract Background Genetic variants associated with acute side effects of radiotherapy in nasopharyngeal carcinoma (NPC) remain largely unknown. Methods We performed a two-stage genome-wide association analysis including a total of 1084 patients, where 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant variants were then validated in an independent cohort of 765 patients using the MassARRAY system. Gene mapping, linkage disequilibrium, genome-wide association analysis, and polygenic risk score were conducted or calculated using FUMA, LDBlockShow, PLINK, and PRSice software programs, respectively. Results Five SNPs (rs6711678, rs4848597, rs4848598, rs2091255, and rs584547) showed statistical significance after validation. Radiotherapy toxicity was more serious in mutant minor allele carriers of all five SNPs. Stratified analysis further indicated that rs6711678, rs4848597, rs4848598, and rs2091255 correlated with skin toxicity in patients of EBV positive, late stage (III and IV), receiving both concurrent chemoradiotherapy and induction/adjuvant chemotherapy, and with OR values ranging from 1.92 to 2.66. For rs584547, high occurrence of dysphagia was found in A allele carriers in both the discovery ( P = 1.27 × 10 − 6 , OR = 1.55) and validation ( P = 0.002, OR = 4.20) cohorts. Furthermore, prediction models integrating both genetic and clinical factors for skin reaction and dysphagia were established. The area under curve (AUC) value of receiver operating characteristic (ROC) curves were 0.657 (skin reaction) and 0.788 (dysphagia). Conclusions Rs6711678, rs4848597, rs4848598, and rs2091255 on chromosome 2q14.2 and rs584547 were found to be novel risk loci for skin toxicity and dysphagia in NPC patients receiving radiotherapy. Trial registration Chinese Clinical Trial Register (registration number: ChiCTR-OPC-14005257 and CTXY-140007-2).
Saracatinib, a Selective Src Kinase Inhibitor, Blocks Fibrotic Responses in Preclinical Models of Pulmonary Fibrosis
Authors: Farida Ahangari, Christine Becker, Daniel G. Foster, Maurizio Chioccioli, Meghan Nelson, Keriann Beke, Xing Wang, Aurelien Justet, Taylor Adams, Benjamin Readhead, Carly Meador, Kelly Correll, Loukia N. Lili, Helen M. Roybal, Kadi-Ann Rose, Shuizi Ding, Thomas Barnthaler, Natalie Briones, Giuseppe DeIuliis, Jonas C. Schupp, Qin Li, Norihito Omote, Yael Aschner, Lokesh Sharma, Katrina W. Kopf, Björn Magnusson, Ryan Hicks, Anna Backmark, Charles S. Dela Cruz, Ivan Rosas, Leslie P. Cousens, Joel T. Dudley, Naftali Kaminski, Gregory P. Downey
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal disorder. Two U.S. Food and Drug Administration-approved antifibrotic drugs, nintedanib and pirfenidone, slow the rate of decline in lung function, but responses are variable and side effects are common. Objectives: Using an in silico data-driven approach, we identified a robust connection between the transcriptomic perturbations in IPF disease and those induced by saracatinib, a selective Src kinase inhibitor originally developed for oncological indications. Based on these observations, we hypothesized that saracatinib would be effective at attenuating pulmonary fibrosis. Methods: We investigated the antifibrotic efficacy of saracatinib relative to nintedanib and pirfenidone in three preclinical models: 1) in vitro in normal human lung fibroblasts; 2) in vivo in bleomycin and recombinant Ad-TGF-β (adenovirus transforming growth factor-β) murine models of pulmonary fibrosis; and 3) ex vivo in mice and human precision-cut lung slices from these two murine models as well as patients with IPF and healthy donors. Measurements and Main Results: In each model, the effectiveness of saracatinib in blocking fibrogenic responses was equal or superior to nintedanib and pirfenidone. Transcriptomic analyses of TGF-β-stimulated normal human lung fibroblasts identified specific gene sets associated with fibrosis, including epithelial-mesenchymal transition, TGF-β, and WNT signaling that was uniquely altered by saracatinib. Transcriptomic analysis of whole-lung extracts from the two animal models of pulmonary fibrosis revealed that saracatinib reverted many fibrogenic pathways, including epithelial-mesenchymal transition, immune responses, and extracellular matrix organization. Amelioration of fibrosis and inflammatory cascades in human precision-cut lung slices confirmed the potential therapeutic efficacy of saracatinib in human lung fibrosis. Conclusions: These studies identify novel Src-dependent fibrogenic pathways and support the study of the therapeutic effectiveness of saracatinib in IPF treatment.
Shining a Light on Cancer—Photonics in Microfluidic Tumor Modeling and Biosensing
Authors: Carlos F. Guimarães, Daniela Cruz‐Moreira, David Caballero, Rogério P. Pirraco, Luca Gasperini, Subhas C. Kundu, Rui L. Reis
Journal: Advanced Healthcare Materials (2022)

Abstract Microfluidic platforms represent a powerful approach to miniaturizing important characteristics of cancers, improving in vitro testing by increasing physiological relevance. Different tools can manipulate cells and materials at the microscale, but few offer the efficiency and versatility of light and optical technologies. Moreover, light‐driven technologies englobe a broad toolbox for quantifying critical biological phenomena. Herein, the role of photonics in microfluidic 3D cancer modeling and biosensing from three major perspectives is reviewed. First, optical‐driven technologies are looked upon, as these allow biomaterials and living cells to be manipulated with microsized precision and present opportunities to advance 3D microfluidic models by engineering cancer microenvironments' hallmarks, such as their architecture, cellular complexity, and vascularization. Second, the growing field of optofluidics is discussed, exploring how optical tools can directly interface microfluidic chips, enabling the extraction of relevant biological data, from single fluorescent signals to the complete 3D imaging of diseased cells within microchannels. Third, advances in optical cancer biosensing are reviewed, focusing on how light–matter interactions can detect biomarkers, rare circulating tumor cells, and cell‐derived structures such as exosomes. Photonic technologies' current challenges and caveats in microfluidic 3D cancer models are overviewed, outlining future research avenues that may catapult the field.
Translatome proteomics identifies autophagy as a resistance mechanism to on-target FLT3 inhibitors in acute myeloid leukemia
Authors: Sebastian E. Koschade, Kevin Klann, Shabnam Shaid, Binje Vick, Jan A. Stratmann, Marlyn Thölken, Laura M. Meyer, The Duy Nguyen, Julia Campe, Laura M. Moser, Susanna Hock, Fatima Baker, Christian T. Meyer, Frank Wempe, Hubert Serve, Evelyn Ullrich, Irmela Jeremias, Christian Münch, Christian H. Brandts
Journal: Leukemia (2022)

Abstract Internal tandem duplications (ITD) in the receptor tyrosine kinase FLT3 occur in 25 % of acute myeloid leukemia (AML) patients, drive leukemia progression and confer a poor prognosis. Primary resistance to FLT3 kinase inhibitors (FLT3i) quizartinib, crenolanib and gilteritinib is a frequent clinical challenge and occurs in the absence of identifiable genetic causes. This suggests that adaptive cellular mechanisms mediate primary resistance to on-target FLT3i therapy. Here, we systematically investigated acute cellular responses to on-target therapy with multiple FLT3i in FLT3-ITD + AML using recently developed functional translatome proteomics (measuring changes in the nascent proteome) with phosphoproteomics. This pinpointed AKT-mTORC1-ULK1-dependent autophagy as a dominant resistance mechanism to on-target FLT3i therapy. FLT3i induced autophagy in a concentration- and time-dependent manner specifically in FLT3-ITD + cells in vitro and in primary human AML cells ex vivo. Pharmacological or genetic inhibition of autophagy increased the sensitivity to FLT3-targeted therapy in cell lines, patient-derived xenografts and primary AML cells ex vivo. In mice xenografted with FLT3-ITD + AML cells, co-treatment with oral FLT3 and autophagy inhibitors synergistically impaired leukemia progression and extended overall survival. Our findings identify a molecular mechanism responsible for primary FLT3i treatment resistance and demonstrate the pre-clinical efficacy of a rational combination treatment strategy targeting both FLT3 and autophagy induction.
New drugs for acute kidney injury
Authors: Peter Pickkers, Patrick T. Murray, Marlies Ostermann
Journal: Intensive Care Medicine (2022)

Acute kidney injury (AKI) is common in critically ill patients and is associated with serious short and longterm complications, including chronic dialysis dependence, and increased mortality [1].There is no approved pharmacological therapy to prevent, treat or enhance recovery from AKI.Current strategies focus predominantly on preventing further deterioration of renal function [2,3].Challenges in determining the exact timing, etiology, and phase of AKI may account for the limited progress in this field.The use of additional biomarkers to define AKI may provide granularity enabling earlier detection [4,5].Nevertheless, research addressing the pathophysiology of AKI has identified potential therapeutic targets, including pathways involved in hemodynamics and oxygen delivery, inflammation, cellular metabolism and oxidative stress, apoptosis, and cellular repair and fibrosis [6].In future, identification of different AKI sub-phenotypes, informed by emerging time-sensitive and AKI phase-specific biomarkers, may aid accelerated and successful drug development in this critical area of unmet need.Here, we describe selected compounds that impact known pathophysiological processes and have been studied in humans (Fig. 1).
Continuous Emotional Support During Labor in a US Hospital
Authors: John Kennell
Journal: JAMA (1991)

The continuous presence of a supportive companion (<i>doula</i>) during labor and delivery in two studies in Guatemala shortened labor and reduced the need for cesarean section and other interventions. In a US hospital with modern obstetric practices, 412 healthy nulliparous women in labor were randomly assigned to a supported group (n = 212) that received the continuous support of a<i>doula</i>or an observed group (n = 200) that was monitored by an inconspicuous observer. Two hundred four women were assigned to a control group after delivery. Continuous labor support significantly reduced the rate of cesarean section deliveries (supported group, 8%; observed group, 13%; and control group, 18%) and forceps deliveries. Epidural anesthesia for spontaneous vaginal deliveries varied across the three groups (supported group, 7.8%; observed group, 22.6%; and control group, 55.3%). Oxytocin use, duration of labor, prolonged infant hospitalization, and maternal fever followed a similar pattern. The beneficial effects of labor support underscore the need for a review of current obstetric practices. (<i>JAMA</i>. 1991;265:2197-2201)
SARS-CoV-2 breakthrough infections in patients with immune-mediated inflammatory diseases during the omicron dominant period
Authors: Laura Boekel, Yaëlle R Besten, Femke Hooijberg, Rosa Wartena, Maurice Steenhuis, Erik Vogelzang, Maureen Leeuw, Sadaf Atiqi, Sander W Tas, Willem F Lems, S Marieke van Ham, Filip Eftimov, Eileen W Stalman, Luuk Wieske, Taco W Kuijpers, Alexandre E Voskuyl, Ronald F van Vollenhoven, Martijn Gerritsen, Charlotte Krieckaert, Theo Rispens, Maarten Boers, Mike T Nurmohamed, Gertjan Wolbink
Journal: The Lancet Rheumatology (2022)
Clinical validation of deep learning algorithms for radiotherapy targeting of non-small-cell lung cancer: an observational study
Authors: Ahmed Hosny, Danielle S Bitterman, Christian V Guthier, Jack M Qian, Hannah Roberts, Subha Perni, Anurag Saraf, Luke C Peng, Itai Pashtan, Zezhong Ye, Benjamin H Kann, David E Kozono, David Christiani, Paul J Catalano, Hugo J W L Aerts, Raymond H Mak
Journal: The Lancet Digital Health (2022)
Sex differences in remission rates over 24 weeks among three different biological treatments compared to conventional therapy in patients with early rheumatoid arthritis (NORD-STAR): a post-hoc analysis of a randomised controlled trial
Authors: Kristina Lend, Ronald F van Vollenhoven, Jon Lampa, Merete Lund Hetland, Espen A Haavardsholm, Dan Nordström, Michael Nurmohamed, Bjorn Gudbjornsson, Anna Rudin, Mikkel Østergaard, Till Uhlig, Gerdur Grondal, Kim Hørslev-Petersen, Marte S Heiberg, Tuulikki Sokka-Isler, Frieda A Koopman, Jos W R Twisk, Irene van der Horst-Bruinsma
Journal: The Lancet Rheumatology (2022)
Efficacy of telemedicine for the management of cardiovascular disease: a systematic review and meta-analysis
Authors: Pei Xuan Kuan, Weng Ken Chan, Denisa Khoo Fern Ying, Mohd Aizuddin Abdul Rahman, Kalaiarasu M Peariasamy, Nai Ming Lai, Nicholas L Mills, Atul Anand
Journal: The Lancet Digital Health (2022)

Telemedicine has been increasingly integrated into chronic disease management through remote patient monitoring and consultation, particularly during the COVID-19 pandemic. We did a systematic review and meta-analysis of studies reporting effectiveness of telemedicine interventions for the management of patients with cardiovascular conditions.
A systematic review of the validity of non-invasive sleep-measuring devices in mid-to-late life adults: Future utility for Alzheimer's disease research
Authors: Sebastian Francis Green, Tory Frame, Luke Vikram Banerjee, Amy Gimson, Jonathan Blackman, Hamish Morrison, Katie Lloyd, Sarah Rudd, William George Frederick Fotherby, Ullrich Bartsch, Shaun Purcell, Matt Jones, Liz Coulthard
Journal: Sleep Medicine Reviews (2022)

Changes in sleep during mid-to-late life are associated with risk for Alzheimer's disease (AD). Mechanistic understanding of this association necessitates measurement tools able to quantify these sleep changes longitudinally and accurately. We conducted a systematic review with meta-analysis of validity studies of non-invasive sleep-measuring devices published since 2015 that record sleep metrics associated with AD in adults over 40 (mean 52.9, SD 6.1 years). We reviewed 52 studies, including 32 wearable and ten non-wearable single or multi-sensor devices validated against polysomnography (minimum one night). The apnoea hypopnoea index and oxygen desaturation index were accurately measured across devices. Total sleep time and sleep efficiency were significantly overestimated (p < 0.001) by mean 33.2 minutes and 7.6%, respectively. Slow wave sleep duration was inaccurately measured except by a headband device with electroencephalography. There was no significant difference in accuracy between participants with and without sleep disorders. Studies were undermined by high risk of bias from closed-access algorithms and classification thresholds, and incomplete reporting of accuracy data. Only one study investigated slow wave activity, and none investigated sleep spindles. Nonetheless, we have identified devices that could be used in future studies of sleep and AD risk and discuss some of the limitations of available research.
Trends in pediatric ambulatory community acquired infections before and during COVID-19 pandemic: A prospective multicentric surveillance study in France
Authors: Pr Robert Cohen, Alexis Rybak, Andreas Werner, Stéphane Béchet, Roxane Desandes, Fréderic Hassid, Jean-Marie André, Nathalie Gelbert, Georges Thiebault, Fabienne Kochert, Fabienne Cahn-Sellem, François Vié Le Sage, Pr François Angoulvant, Naïm Ouldali, Bruno Frandji, Corinne Levy
Journal: The Lancet Regional Health - Europe (2022)

Covid-19 pandemic control has imposed several non-pharmaceutical interventions (NPIs). Strict application of these measures has had a dramatic reduction on the epidemiology of several infectious diseases. As the pandemic is ongoing for more than 2 years, some of these measures have been removed, mitigated, or less well applied. The aim of this study is to investigate the trends of pediatric ambulatory infectious diseases before and up to two years after the onset of the pandemic.We conducted a prospective surveillance study in France with 107 pediatricians specifically trained in pediatric infectious diseases. From January 2018 to April 2022, the electronic medical records of children with an infectious disease were automatically extracted. The annual number of infectious diseases in 2020 and 2021 was compared to 2018-2019 and their frequency was compared by logistic regression.From 2018 to 2021, 185,368 infectious diseases were recorded. Compared to 2018 (n=47,116) and 2019 (n=51,667), the annual number of cases decreased in 2020 (n=35,432) by about a third. Frequency of scarlet fever, tonsillopharyngitis, enteroviral infections, bronchiolitis, and gastroenteritis decreased with OR varying from 0·6 (CI95% [0·5;0·7]) to 0·9 (CI95% [0·8;0·9]), p<0·001. In 2021, among the 52,153 infectious diagnoses, an off-season rebound was observed with increased frequency of enteroviral infections, bronchiolitis, gastroenteritis and otitis with OR varying from 1·1 (CI95% [1·0;1·1]) to 1·5 (CI95% [1·4;1·5]), p<0·001.While during NPIs strict application, the overall frequency of community-acquired infections was reduced, after relaxation of these measures, a rebound of some of them (enteroviral infections, bronchiolitis, gastroenteritis, otitis) occurred beyond the pre-pandemic level. These findings highlight the need for continuous surveillance of infectious diseases, especially insofar as future epidemics are largely unpredictable.ACTIV, AFPA, GSK, MSD, Pfizer and Sanofi.
First-Line Systemic Therapies for Advanced Hepatocellular Carcinoma: A Systematic Review and Patient-Level Network Meta-Analysis
Authors: Khi Yung Fong, Joseph Jonathan Zhao, Rehena Sultana, Joycelyn Jie Xin Lee, Suat Ying Lee, Stephen Lam Chan, Thomas Yau, David Wai Meng Tai, Raghav Sundar, Chow Wei Too
Journal: Liver Cancer (2022)

Introduction: Sorafenib was historically the standard of care for advanced hepatocellular carcinoma (aHCC) until it was superseded by the combination of atezolizumab and bevacizumab. Thereafter, several novel first-line combination therapies have demonstrated favorable outcomes. The efficacies of these treatments in relation to current and previous standards of care are unknown, necessitating an overarching evaluation. Methods: A systematic literature search was conducted on PubMed, EMBASE, Scopus, and the Cochrane Controlled Register of Trials for phase III randomized controlled trials investigating first-line systemic therapies for aHCC. Kaplan-Meier curves for overall survival (OS) and progression-free survival (PFS) were graphically reconstructed to retrieve individual patient-level data. Derived hazard ratios (HRs) for each study were pooled in a random-effects network meta-analysis (NMA). NMAs were also conducted using study-level HRs for various subgroups, according to viral etiology, Barcelona Clinic Liver Cancer (BCLC) staging, alpha-fetoprotein (AFP) levels, macrovascular invasion, and extrahepatic spread. Treatment strategies were ranked using p scores. Results: Among 4,321 articles identified, 12 trials and 9,589 patients were included for analysis. Only two therapies showed OS benefit over sorafenib: combined anti-programmed-death and anti-VEGF pathway inhibitor monoclonal antibodies (Anti-PD-(L)1/VEGF Ab), including atezolizumab-bevacizumab and sintilimab-bevacizumab biosimilar (HR = 0.63, 95% CI = 0.53–0.76) and tremelimumab-durvalumab (HR = 0.78, 95% CI = 0.66–0.92). Anti-PD-(L)1/VEGF Ab showed OS benefit over all other therapies except tremelimumab-durvalumab. Low heterogeneity (I2 = 0%) and inconsistency (Cochran’s Q = 0.52, p = 0.773) was observed. p scores for OS ranked Anti-PD-(L)1/VEGF Ab as the best treatment in all subgroups, except hepatitis B where atezolizumab-cabozantinib ranked highest for both OS and PFS, as well as nonviral HCC and AFP ≥400 μg/L where tremelimumab-durvalumab ranked highest for OS. Conclusion: This NMA supports Anti-PD-(L)1/VEGF Ab as the first-line therapy for aHCC and demonstrates a comparable benefit for tremelimumab-durvalumab which also extends to certain subgroups. Results of the subgroup analysis may guide treatment according to baseline characteristics, while pending further studies.
Hepatitis B Virus Treatment and Hepatocellular Carcinoma: Controversies and Approaches to Consensus
Authors: Soo Ki Kim, Takako Fujii, Soo Ryang Kim, Atsushi Nakai, Young-Suk Lim, Satoru Hagiwara, Masatoshi Kudo
Journal: Liver Cancer (2022)

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Long-term therapy with nucleos(t)ide analogs (NAs) such as entecavir (ETV) and tenofovir disoproxil fumarate (TDF) favorably affects the incidence of hepatocellular carcinoma (HCC) on the basis of data from randomized or matched control studies. Recent data suggest a lower HCC incidence after 5 years of ETV or TDF therapy in chronic hepatitis B (CHB) patients, especially those with baseline cirrhosis. &lt;b&gt;&lt;i&gt;Summary:&lt;/i&gt;&lt;/b&gt; Three controversial issues remain to be resolved regarding hepatitis B virus (HBV) treatment and HCC. (1) The efficacy of antiviral treatment for the prevention of HCC is not established. The guidelines of the American Association for the Study of Liver Diseases (AASLD), the Asian Pacific Association for the Study of the Liver (APASL), and the European Association for the Study of the Liver (EASL) for the management of HBV infection state that antiviral treatment of HBV with interferon and NAs prevents the development of HCC. Among experts in CHB treatment, however, there is disagreement on the HCC prevention effects of antiviral treatment. (2) The rationale for antiviral management in patients with high HBV DNA and normal levels of alanine aminotransferase is unclear. The AASLD, EASL, and APASL guidelines do not recommend antiviral treatment for immune-tolerant CHB patients, and the terms and methods of treating such patients remain to be clarified. (3) The efficacy of first-line treatment with NAs, including ETV, TDF, and tenofovir alafenamide fumarate (TAF), to prevent HCC in CHB patients remains unknown. Several studies have produced controversial results regarding the effects of NAs on the risk and prevention of HCC. In the present review, we discuss these 3 issues, citing recent studies and clinical management guidelines from major international associations. &lt;b&gt;&lt;i&gt;Key Messages:&lt;/i&gt;&lt;/b&gt; Suggested approaches for reaching a consensus including applying the propensity score matching method, performing randomized controlled studies, and performing clinical studies with larger numbers of subjects and longer follow-up.